CLINICAL TRIAL published: 31 October 2016 doi: 10.3389/fonc.2016.00232 Randomized Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in Squamous Cell Carcinoma of the Head and Neck (MEHGAN Study) Jérôme Fayette1*, Lori Wirth2, Cristina Oprean3, Anghel Udrea4, Antonio Jimeno5, Danny Rischin6, Christopher Nutting7, Paul M. Harari8, Tibor Csoszi9, Dana Cernea10, Paul O’Brien11, William D. Hanley12, Amy V. Kapp12, Maria Anderson12, Elicia Penuel12, Bruce McCall12, Andrea Pirzkall12 and Jan B. Vermorken13 1 Centre Léon Bérard, Université de Lyon, Lyon, France, 2 Massachusetts General Hospital, Boston, MA, USA, 3 Oncomed SRL, Timisoara, Romania, 4 Medisprof SRL, Cluj-Napoca, Romania, 5 University of Colorado Cancer Center, Aurora, CO, Edited by: USA, 6 Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia, 7 Royal Marsden NHS Trust, Elise Kohn, The Institute of Cancer Research London, Sutton, UK, 8 University of Wisconsin Hospital and Clinics, Madison, WI, USA, 9 10 National Cancer Institute, USA Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház, Szolnok, Hungary, Institutul Oncologic Prof. Dr. Ion Chiricuta 11 12 Reviewed by: Cluj-Napoca, Cluj-Napoca, Romania, Medical University of South Carolina, Charleston, SC, USA, Genentech, South San 13 Susumu Okano, Francisco, CA, USA, Antwerp University Hospital, Edegem, Belgium National Cancer Centre Hospital East, Japan Background: Duligotuzumab, a novel dual-action humanized IgG1 antibody that blocks Kenji Okami, Tokai University, Japan ligand binding to epidermal growth factor receptor (EGFR) and human epidermal growth *Correspondence: factor receptor 3 (HER3), inhibits signaling from all ligand-dependent HER dimers, and Jérôme Fayette can elicit antibody-dependent cell-mediated cytotoxicity. High tumor-expression of [email protected] neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab. Specialty section: Methods: This multicenter, open-label, randomized phase II study (MEHGAN) evaluated This article was submitted to Head and Neck Cancer, drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the a section of the journal head and neck (SCCHN) progressive on/after chemotherapy and among patients with Frontiers in Oncology NRG1-high tumors. Patients received duligotuzumab (1100 mg IV, q2w) or cetuximab Received: 29 August 2016 (400 mg/m2 load, 250 mg/m2 IV, q1w) until progression or intolerable toxicity. Tumor Accepted: 14 October 2016 Published: 31 October 2016 samples were assayed for biomarkers [NRG1, ERBB3, and human papillomavirus (HPV) Citation: status]. Fayette J, Wirth L, Oprean C, Udrea A, Jimeno A, Rischin D, Results: Patients (N = 121) were randomized (duligotuzumab:cetuximab; 59:62), Nutting C, Harari PM, Csoszi T, median age 62 years; ECOG 0–2. Both arms (duligotuzumab vs. cetuximab, respec- Cernea D, O’Brien P, Hanley WD, Kapp AV, Anderson M, Penuel E, tively) showed comparable progression-free survival [4.2 vs. 4.0 months; HR: 1.23 (90% McCall B, Pirzkall A and confidence interval (CI): 0.89–1.70)], overall survival [7.2 vs. 8.7 months; HR 1.15 (90% Vermorken JB (2016) Randomized CI: 0.81–1.63)], and objective response rate (12 vs. 14.5%), with no difference between Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in patients with NRG1-high tumors or ERBB3-low tumors. Responses in both arms were Squamous Cell Carcinoma of the confined to HPV-negative patients. Grade≥ 3 adverse events (AEs) (duligotuzumab vs. Head and Neck (MEHGAN Study). Front. Oncol. 6:232. cetuximab, respectively) included infections (22 vs. 11.5%) and GI disorders (17 vs. 7%), doi: 10.3389/fonc.2016.00232 contributing to higher rates of serious AEs (41 vs. 29.5%). Metabolic disorders were less Frontiers in Oncology | www.frontiersin.org 1 October 2016 | Volume 6 | Article 232 Fayette et al. Duligotuzumab in Second-Line SCCHN frequent with duligotuzumab (10 vs. 16%); any grade rash-related events were less with duligotuzumab (49 vs. 67%). Conclusion: While several lines of preclinical evidence had supported the premise that the blockade of HER3 in addition to that of EGFR may improve outcomes for patients with R/M SCCHN overall or specifically in those patients whose tumors express high levels of NRG1, this study provided definitive clinical evidence refuting this hypothesis. Duligotuzumab did not improve patient outcomes in comparison to cetuximab despite frequent expression of NRG1. These data indicate that inhibition of EGFR alone is suffi- cient to block EGFR–HER3 signaling, suggesting that HER2 plays a minimal role in this disease. Extensive biomarker analyses further show that HPV-negative SCCHN but not HPV-positive SCCHN are most likely to respond to EGFR blockage by cetuximab or duligotuzumab. Keywords: NRG1, HER3, EGFR, SCCHN, HPV, duligotuzumab, MEHD7945A, cetuximab INTRODUCTION Duligotuzumab (MEHD7945A) is a novel dual-action human IgG1 monoclonal antibody that simultaneously targets HER3 and Multiple members of the HER family receptor tyrosine kinases, EGFR (15). HER3 is encoded by the ERBB3 gene. Duligotuzumab including epidermal growth factor receptor (EGFR), HER1, and demonstrated superior activity compared with mono-specific HER2, are established therapeutic targets in several epithelial EGFR- or HER3-targeting antibodies in the non-clinical FaDu malignancies (1). EGFR is a rational focus for squamous cell SCCHN model (16), as well as in human xenograft models derived carcinoma of the head and neck (SCCHN) given the prevalence from SCCHN and NSCLC tumors with acquired resistance to of its overexpression and crucial role in SCCHN pathogenesis EGFR inhibitors (17). Preliminary evidence of clinical activity (2, 3). Moreover, EGFR is a clinically validated therapeutic target included two confirmed partial responses (PRs) in SCCHN in recurrent/metastatic SCCHN with approval of cetuximab as a patients (18) who had entered the duligotuzumab phase Ia study single agent (4), concurrent with platinum-based chemotherapy after progressing on prior therapy, one having relapsed after (5), and in combination with radiotherapy in the curative SCCHN multiple prior treatment regimens including an EGFR inhibitor. setting (6). Many SCCHN patients do not respond to cetuximab Both patients’ tumors were found to have NRG1 expression near therapy, and for those who do, they commonly manifest acquired the top of the range observed in the analysis of tumor samples resistance following prolonged exposure to the drug. These described above. findings have prompted the design of next-generation EGFR Taken together, these observations suggested that the addi- inhibitors and approaches that may serve to overcome resistance tion of HER3 blockade to EGFR blockade with duligotuzumab to cetuximab. may improve clinical outcomes in patients with recurrent or Factors thought to contribute to cetuximab resistance in metastatic (R/M) SCCHN overall or specifically in those patients SCCHN patients include upregulation of ligands for EGFR whose tumors express high levels of NRG1. This phase II study and human epidermal growth factor receptor 3 (HER3) evaluated the efficacy of duligotuzumab vs. cetuximab in patients (7, 8), heterodimerization of EGFR and HER2 with HER3 (9), with R/M SCCHN progressive on/after chemotherapy and overexpression of HER2 and HER3 (10), and overexpression included post hoc analyses by NRG1 expression levels, ERBB3 and aberrant nuclear localization of EGFR (11). Interestingly, expression levels, and human papillomavirus (HPV) status. a subset of SCCHN cell lines are resistant to anti-EGFR tyros- ine kinase inhibitor (TKI) treatment and do not overexpress METHODS HER2 but are sensitive to combined anti-EGFR/anti-HER2 TKI inhibition (12). Many of these cell lines were found to Patients have high expression of heregulin (HRG), the ligand binding to Eligible patients were ≥18 years of age with histologically HER3, and activation of HER3 signaling. It was hypothesized confirmed R/M SCCHN who had progressed after one or more that such cells may escape the effects of anti-EGFR therapy via lines of treatment, at least one platinum-based regimen for R/M HRG-dependent signaling of a HER2/HER3 dimer. An analysis disease, and not suitable for local therapy. Patients with ECOG of >700 tumor samples from patients with non-small cell lung performance status of 0, 1, or 2, disease measurable per RECIST cancer (NSCLC), SCCHN, colorectal, breast, or ovarian cancer v1.1, adequate hematologic, renal, or hepatic function, no prior found that median HRG mRNA expression is significantly HER targeted therapy with exception of EGFR inhibitor given higher in SCCHN tumors than in the other tumor types (13). in upfront setting and as long as discontinued ≥3 months prior HRG represents alpha and beta forms of neuregulin 1 (14) and to enrollment were included. Patients were excluded if they is here forth referred to as NRG1. had nasopharyngeal cancer. Frontiers in Oncology | www.frontiersin.org 2 October 2016 | Volume 6 | Article 232 Fayette et al. Duligotuzumab in Second-Line SCCHN Study Design in R/M SCCHN patients. Institutional review boards at all par- This was a phase II, randomized, multicenter, open-label study ticipating institutions approved the study protocol. All patients with two arms (Figure 1) assessing duligotuzumab vs. cetuximab gave written informed consent. The study was conducted FIGURE 1 | Study design. Frontiers in Oncology | www.frontiersin.org 3 October 2016 | Volume 6 | Article 232 Fayette et